Ying Wang1,2, Soichi Sano1, Kosei Oshima3, Miho Sano1, Yosuke Watanabe4, Yasufumi Katanasaka3, Yoshimitsu Yura1, Changhee Jung1,5, Atsushi Anzai6, Filip K Swirski6, Noyan Gokce7,8, Kenneth Walsh1. 1. Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville (Y. Wang, S.S., M.S., Y.Y., C.J., K.W.). 2. The First Affiliated Hospital of Chongqing Medical University, People's Republic of China (Y. Wang). 3. Molecular Cardiology (K.O., Y.K.), Boston University School of Medicine, MA. 4. Whitaker Cardiovascular Institute, and Vascular Biology Section (Y. Watanabe), Boston University School of Medicine, MA. 5. Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea (C.J.). 6. Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston (A.A., F.K.S.). 7. Cardiovascular Medicine (N.G.), Boston University School of Medicine, MA. 8. Cardiology, Boston Medical Center, MA (N.G.). Dr Watanabe is currently at the Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, Chuo, Yamanashi, Japan. Dr Katanasaka is currently at the Division of Molecular Medicine, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Japan. Dr Anzai is currently at the Department of Cardiology, Keio University, School of Medicine, Tokyo, Japan.
Abstract
BACKGROUND: Although the complex roles of macrophages in myocardial injury are widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. METHODS: To examine the regulation and function of neutrophils in pressure overload-induced cardiac hypertrophy, mice underwent treatment with Ly6G antibody to deplete neutrophils and then were subjected to transverse aortic constriction. RESULTS: Neutrophil depletion diminished transverse aortic constriction-induced hypertrophy and inflammation and preserved cardiac function. Myeloid deficiency of Wnt5a, a noncanonical Wnt, suppressed neutrophil infiltration to the hearts of transverse aortic constriction-treated mice and produced a phenotype that was similar to the neutropenic conditions. Conversely, mice overexpressing Wnt5a in myeloid cells displayed greater hypertrophic growth, inflammation, and cardiac dysfunction. Neutrophil depletion reversed the Wnt5a overexpression-induced cardiac pathology and eliminated differences in cardiac parameters between wild-type and myeloid-specific Wnt5a transgenic mice. CONCLUSIONS: These findings reveal that Wnt5a-regulated neutrophil infiltration has a critical role in pressure overload-induced heart failure.
BACKGROUND: Although the complex roles of macrophages in myocardial injury are widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. METHODS: To examine the regulation and function of neutrophils in pressure overload-induced cardiac hypertrophy, mice underwent treatment with Ly6G antibody to deplete neutrophils and then were subjected to transverse aortic constriction. RESULTS: Neutrophil depletion diminished transverse aortic constriction-induced hypertrophy and inflammation and preserved cardiac function. Myeloid deficiency of Wnt5a, a noncanonical Wnt, suppressed neutrophil infiltration to the hearts of transverse aortic constriction-treated mice and produced a phenotype that was similar to the neutropenic conditions. Conversely, mice overexpressing Wnt5a in myeloid cells displayed greater hypertrophic growth, inflammation, and cardiac dysfunction. Neutrophil depletion reversed the Wnt5a overexpression-induced cardiac pathology and eliminated differences in cardiac parameters between wild-type and myeloid-specific Wnt5atransgenic mice. CONCLUSIONS: These findings reveal that Wnt5a-regulated neutrophil infiltration has a critical role in pressure overload-induced heart failure.
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